59

Abstract: Dental caries is an infectious and

transmissible disease, in which many genetic,
environmental and behavioral risk factors interact.
The mutans streptococci (MS), mainly Streptococcus
mutans and Streptococcus sobrinus are the micro-
organisms most strongly associated with this disease.
The main virulence factors associated with MS
cariogenicity include adhesion, acidogenicity and acid
tolerance. These properties work together to modify the
physico-chemical properties of the biofilm, resulting in
ecological changes in the form of increased proportions
of S. mutans and other acidogenic and aciduric species.
In addition, reports of higher numbers of S. mutans
genotypes with increased virulence in caries-active
subjects suggest the importance of microenvironmental
factors in increasing the risk of caries. This review
focuses on the transmission and establishment of
different genotypes of S. mutans and the role they play
in the development of dental caries. (J. Oral Sci. 47,
59-64, 2005)
Keywords: Streptococcus mutans; dental caries;
genotypes; mutacin; glucosyltransferase;
review.
Introduction
Dental caries is a transmissible infectious disease in
which mutans streptococci (MS) play the major role. As
in many infectious diseases, colonization by pathogens is
required before the disease can occur. MS are generally
considered to be the principal etiological agent of dental
caries (1).
There is a range of virulence factors important for the
establishment of MS in the complex microbial community
of dental biofilm. Studies of the virulence factors of S.
mutans and their correlation with species biodiversity are
fundamental to understanding the role played by
colonization by different genotypes in the same individual,
and the expression of characteristics that may or may not
influence their virulence capacity and survival ability
under different environmental conditions.
Colonization, transmissibility and
stability of S. mutans in the oral cavity
Studies using phenotyping and/or genotyping methods
strongly suggest that the mother is the major primary
source of infection for children who carry S. mutans and/or
S. sobrinus strains (2-10), and the saliva is the principal
vehicle by which transfer of MS may occur (10-12).
However, detection of genotypes that are not found in
childrens mothers or other family members indicates that
S. mutans and/or S. sobrinus may also be acquired from
other sources (5,7,8,10,12).
Furthermore, variability in transmission can be associated
with childrens individual susceptibilities, including the
period defined as the window of infectivity (13), which
was reported to occur earlier in Brazilian children (14,15);
the number of erupted teeth (13,15,16); the emergence of
Journal of Oral Science, Vol. 47, No. 2, 59-64, 2005
Correspondence to Dr. Reginaldo B. Gonalves, Department of
Oral Diagnostics, Faculty of Dentistry of Piracicaba, University
of Campinas, Piracicaba, So Paulo, Brazil Av. Limeira, 901 -
Areio - Piracicaba, So Paulo, Brazil
13414-903 - Caixa Postal 052
Tel: + 55-19-3412-5379
Fax: + 55-19-3412-5218
E-mail: reginald@fop.unicamp.br
Transmission, diversity and virulence factors
of Streptococcus mutans genotypes
Marcelo Henrique Napimoga, Jose Francisco Hfling, Marlise Inez Klein,
Regianne Umeko Kamiya and Reginaldo Bruno Gonalves
Department of Oral Diagnostics, Faculty of Dentistry of Piracicaba,
University of Campinas, Piracicaba, So Paulo, Brazil
(Received 3 December 2004 and accepted 9 April 2005)
Review
60
molars (13); the presence of enamel hypoplasia (17);
sucrose consumption (14); the action of nonspecific factors
of the salivary and mucosal immune systems (3); and
immunological conditions in children (18).
It has been observed that children harbor one to five
distinct genotypes of MS at different ages (4-7,10,12,19-
21). The MS genotypic diversity in four sampling sites
(saliva, tongue dorsum, alveolar ridge mucosa, dental
biofilm) from childrens oral cavities was shown to be
homogeneous; however, the dental biofilm was an important
site given the greater number of MS genotypes and strains
isolated (10). Studies of the initial colonization by MS
indicate that these bacteria require non-shedding tooth
surfaces to become established in the oral cavity (16).
More sensitive methods using DNA specific probes indicate
that the retentive surfaces of the tongue dorsum may
function as a reservoir for posterior tooth colonization
(22).
Nevertheless, few data are available about the stability
of the genotypes detected at the time of initial acquisition.
Previous studies suggested that early colonizing MS strains
might be stable in the mouth for many years, although some
genotypes detected in childhood could not be recovered
in later years (8-10,19,23).
Klein et al. (10) identified a total of 52 distinct genotypes
in children, but mothers transmitted only 16 of them.
However, a tendency toward effective stability of genotypes
transmitted by mothers was observed (10). One explanation
for this selective colonization is that the immune response
to a successfully colonizing maternal genotype may
interfere with colonization of other genotypes, making
colonization less likely (3,18). The maternal role in infection
also suggests that the contacts responsible for salivary
transmission of these organisms can also provide frequent
immunological exposure to bacterial antigens (18). The
mechanisms of action of salivary IgA antibodies against
MS include interference with their sucrose-independent
and sucrose-dependent attachments to, and accumulation
on, tooth surfaces, as well as possible inhibition of their
metabolic activities (24).
Alaluusua et al. (25) demonstrated a high degree of
homology between MS strains recovered among members
of the same family, indicating both vertical and horizontal
routes of transmission, and persistent colonization by
early acquired MS until young adulthood. It was also
shown that isolates that had similar genetic fingerprints
(transmitted strains) had similar expression of gluco-
syltransferase (GTF). One case was reported of a similar
S. mutans genotype colonizing two children from unrelated
families attending the same Brazilian nursery (12). In
addition, a study of 39 Japanese children from a day
nursery found that six of them shared the same strain type
of MS (26). Taken together, these results suggest that
horizontal transmission may also occur.
Some previous work has shown greater genetic variability
of S. mutans in nursing-bottle caries than in healthy
children; however, a positive relationship between caries
activity and the genetic diversity of S. mutans is still
controversial. Alaluusua et al. (4) suggested that caries-
active children with high sucrose consumption carry greater
ribotype diversity of MS compared with caries-free
children. On the other hand, Kreulen et al. (21) showed a
negative correlation between caries activity and genotypic
diversity.
The ability of bacteria to survive and persist in a given
environment will depend, in part, on their inherent genetic
plasticity, which determines their ability to respond to
fluctuating local environmental conditions or stresses (27).
The microbiota resident in the oral biofilm are subjected
to many variable environmental stresses, including the
availability or lack of nutrients, acidic pH, and exposure
to organic acids (28,29). Paddick et al. (30) showed that
the proportions of MS and lactobacilli were elevated in the
biofilm of caries-active subjects, while A. naeslundii
isolates formed a significantly greater proportion of the
microbiota in samples from caries-free subjects. These
observations support the assertion that the biofilm samples
from the two subject populations were exposed to different
environments and, consequently, to different stresses.
In a recent study of young adults, Redmo-Emanuelsson
et al. (31) found a maximum of seven genotypes in subjects
who had previous caries experience. This study is consistent
with our findings of a maximum of eight genotypes in
caries-active young subjects using AP-PCR (32). The
existence of several genotypes in biofilm could merely be
a consequence of favorable circumstances for MS in
biofilm, but it is possible that the simultaneous action of
different genotypes with distinct virulence potential further
increases the risk of caries. Nascimento et al. (33) found
that S. mutans was more prevalent in coronal than root
dental biofilm, but no difference was found between root
and coronal caries lesions. Furthermore, the maximum
number of S. mutans genotypes found together at a specific
site was five and the same genotype could be found at more
than one oral site.
Adhesion
Biofilm development occurs in two distinct phases:
during the first, bacterial surface proteins interact with host
or bacterial products adsorbed on the tooth surface. In the
second phase, biofilm forms as bacteria accumulate by
aggregation with the same or other species and produce
61
an extracellular polysaccharide matrix (34). Genetic
differences may relate to differences in virulence between
MS strains. One important characteristic of S. mutans in
promoting caries development is the ability to adhere
firmly to the tooth surface in the presence of sucrose (25),
and this adherence is mediated mainly by the enzymatic
action of the GTF enzymes (1,35). These enzymes are
considered fundamental for the virulence of S. mutans in
the pathogenesis of dental caries (36). Previous research
has shown differences in virulence factors among S. mutans
isolates (32,37,38). Differences in the synthesis of water
insoluble-glucan (WIG) or biofilm formation between
genotypes could be associated with different levels of
virulence. This is important, since it has been demonstrated
that WIG produced from sucrose modifies the physico-
chemical properties of dental plaque, including low
inorganic concentrations of calcium, phosphorus and
fluoride (39) and increased porosity of the dental plaque
matrix (40), making it more cariogenic.
Bacteria are known to regulate diverse physiological
processes through a mechanism called quorum sensing (41).
The com system, which controls genetic competence
development in response to the concentration of the
competence-stimulating peptide, is also involved in biofilm
formation and the biofilm architecture of S. mutans. This
cell-cell signaling system involves several gene products
encoded by cslAB (comAB) (42) and comCDE (43). This
quorum-sensing system functions optimally when the
cells are living in actively growing biofilms (43), suggesting
that the cell-cell signaling system might play a role in the
formation of S. mutans biofilms. A recent study described
the effects of mutations in several comloci with regard to
biofilm formation. The results clearly showed that
inactivation of any one of the genes encoding the
components of the quorum-sensing system, in particular
comC, results in the formation of an abnormal biofilm (44).
Recent studies have shown that luxS is involved in global
regulation of physiological functions and virulence. Also,
luxS inactivation resulted in decreased expression of several
genes that encode membrane-associated proteins, including
BrpA and Ffh, which have been shown to play roles in
envelope integrity and acid tolerance (45).
Other bacterial components associated with the
accumulation phase of MS are proteins that bind glucan.
At least three S. mutans glucan binding proteins (Gbp) have
been identified: GbpA (46), GbpB (47), and GbpC (48).
Although over the years numerous surface or secreted
products of MS have been proposed as vaccine antigen
candidates, attention has recently focused on three protein
antigens: the surface fibrilar adhesins known as AgI/II (or
SpaP, PAc), the glucosyltransferases and the glucan-
binding proteins (49). Numerous experiments in a variety
of animal models comprising rodents and primates have
demonstrated the induction of salivary S-IgA and circulating
IgG antibodies to MS antigens by oral or intranasal
immunization with AgI/II, GTF or Gbps (24,50-52).
Immunization of mice with synthetic peptides (residues
301-319) from the alanine-rich region of antigen I/II
suppressed tooth colonization with S. mutans (53).
Intranasal immunization with antigen I/II, coupled with
the cholera toxin B subunit, suppressed colonization of
mouse teeth by S. mutans (53). Although the basic principle
of immune protection from dental caries caused by MS
has been established in pre-clinical studies, the effective
application of this approach to humans needs further
refinement (54). Furthermore, in experimental infection
of rats, systemic or mucosal immunization with GbpB
induced protective immunity to dental caries, indicating
that GbpB may be an important target for the development
of caries vaccines (55).
Mutacin
The role of mutacins in vivo is unclear, however the
antimicrobial activity of these substances may confer an
ecological advantage for the producing strain in bacterial
communities such as dental biofilm (56), and they may also
be important for the establishment of S. mutans in vivo
(56,57).
Mutacins are peptide or protein antibiotics that are
mainly bactericidal for other bacteria of the same or closely
related species, as well as for other Gram-positive
microorganisms, and are likely to confer an ecological
advantage in diverse bacterial communities such as dental
biofilm (56). The relationship between caries activity and
the higher synthesis of some virulence factors by different
genotypes of S. mutans has been demonstrated in the
literature (32,37).
The mutacin activity of S. mutans may facilitate the
transmission of the species between mother and child and
increase the ratio of this species in the dental biofilm,
contributing to increased risk of caries (6). However, some
studies found no association between the inhibitory
spectrum of mutacins and infecting levels of MS or caries
incidence, suggesting that mutacin production may not be
relevant in the ability of S. mutans to colonize the host and
induce disease (58,59).
In a recent study, Kamiya et al. (60) showed distinct
mutacin production profiles between S. mutans isolated
from caries-active and caries-free individuals, which can
be related to different colonization profiles described in
these individuals. Mutacins could play an important
biological role in the regulation and composition of dental
62
biofilm due to their synergistic or antagonistic activity,
suggesting that wide spectrum mutacins may be more
important in the colonization and stabilization of this
cariogenic species, mainly in the stable niche of highly
complex microbial activity (60).
Conclusion
The identification of the source of MS transmission is
essential to the development of strategies for the prevention
of dental caries. The early acquisition of MS by infants
occurs mainly via the mothers saliva, and probably also
by other sources of transmission. Immunological
interception of the initial attempts of MS to colonize the
tooth surface would seem to be the preferred vaccine
strategy. Successful establishment of MS in infancy appears
to lead to colonization of the permanent dentition by MS
and their persistence into adulthood. In addition to
environmental and host factors, identification of specific
pathogenic genotypes of S. mutans that may be more
virulent colonizers might predict sites that are more
susceptible to disease.
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